Infiltration of immune cells into the kidney is important in the development of hypertension and kidney disease in humans and animals. Preliminary and published data from this PPG have demonstrated that increasing the sodium intake to Dahl Salt-Sensitive (SS) rats results in the infiltration of immune cells and elevation of O2 and H2O2 in the renal medulla which accompany the development of hypertension and kidney damage. Other studies demonstrated that genetic mutation of recombination activating gene 1 (Rag1) or chronic immunosuppressive therapy in SS rats decreased immune cell infiltration and attenuated salt-sensitive hypertensive and renal disease. Furthermore, infiltrating immune cells are enriched in NADPH oxidase and can therefore serve as a source of reactive oxygen species. Supporting a role of the immune system in human hypertension, Genome Wide Association Studies demonstrated that mutations in Sh2b3, a gene important in T-lymphocyte signaling, are associated with hypertension and kidney disease in patients. Sh2b3 is a known intracellular signaling molecule in T-lymphocytes and endothelial cells, but the mechanisms of its effects to alter blood pressure and renal disease are unknown. Intriguing preliminary data demonstrate that genetic mutation of Sh2b3 in the SS rat alters renal T-cell infiltration, changes the inflammatory cytokine profile in the kidney, and attenuates hypertension and renal damage in SS rats fed high salt. Based upon our preliminary data, we propose that the infiltrating immune cells in the kidney, specifically T-lymphocytes, exert deleterious actions by releasing H2O2 and cytokines in the kidney to accelerate the ongoing disease process. The mechanisms of action of infiltrating T-cells will be explored in this proposal using a comprehensive approach with newly generated rat models in which Rag1 (SSRag1 null), Sh2b3 (SSSh2b3 mutant), and the p67phox subunit of NADPH oxidase (SSp67 null) have been mutated in the SS rat. Experiments in this proposal will test the general hypothesis that infiltration of T-cells in the kidney exaggerates salt-sensitive hypertension and renal disease by increasing free radicals and cytokines. As a corollary to this hypothesis, we propose to elucidate the mechanisms of action of Sh2b3 in salt-sensitive hypertension. This hypothesis will be tested in three, mechanistically-based, Specific Aims. Aim 1 will use SSp67 null and SSRag1 null rats to test the hypothesis that NADPH oxidase in the infiltrating immune cells increases H2O2 which amplifies SS hypertension and renal injury and blunts pressure natriuresis. Aim 2 will use SSRag1 null rats to test the hypothesis that T-lymphocyte infiltration into the kidney alters the cytokine milieu and is sufficient to amplify the development of SS hypertension and kidney damage. Aim 3 will study SSSh2b3 mutant rats to test the hypothesis that Sh2b3 mediates its actions by altering infiltration of T-cells and cytokine/free radical release in the kidney. These three integrative aims will be addressed with a comprehensive approach ranging from cellular and molecular mechanisms to whole animal physiology and pathophysiology using unique animal models. Each mechanistic aim is strongly supported by preliminary data.